The TGF-beta pathway controls a broad range of cellular behavior including cell proliferation, differentiation, and apoptosis of various cell types including tumor cells, endothelial cells, immune cells, and fibroblasts. Besides TGF-beta's direct effects on tumor growth and its involvement in neoangiogenesis have received recent attention. Germline mutations in TGF-beta receptors or coreceptors causing Hereditary Hemorrhagic Teleangiectasia and the Loeys-Dietz syndrome underline the involvement of TGF-beta in vessel formation and maturation. Several therapeutic approaches are evaluated at present targeting the TGF-beta pathway including utilization of antisense oligonucleotides against TGF-beta itself or antibodies or small molecule inhibitors of TGF-beta receptors. Some of these therapeutic agents have already entered the clinical arena including an antibody against the endothelium specific TGF-beta class I receptor ALK-1 targeting tumor vasculature. In conclusion, therapeutic manipulation of the TGF-beta pathway opens great opportunities in future cancer therapy.